Immunoglobulin (Ig) is a generic term for antibodies and proteins structurally or functionally related to the antibodies. That is, when an antigen to which an immunoglobulin binds has been revealed, the immunoglobulin is called an antibody in association with the particular antigen. In a basic molecular structure of the immunoglobulin, two each of two kinds (small and large) of polypeptides, i.e., light chains (also referred to as L chains) and heavy chains (also referred to as H chains) are linked together by disulfide bonds. The heavy chain has a structure consisting of a constant region (also referred to as C region) comprised of three domains (CH1, CH2, and CH3) and a variable region (also referred to as V region) comprised of a VH domain, both regions of which is being linked together. In the immunoglobulin except IgM and IgE, there is a peptide called a hinge region between CH1 and CH2. The light chain has a structure consisting of a constant region comprised of a CL domain and a variable region comprised of a VL domain, both regions of which are being linked together. The variable regions are found to have diversity in amino acid sequence, and thus various antibodies against various antigens are produced in a living body.
A hitherto clinically used immunoglobulin preparation is a blood preparation obtained by concentrating immunoglobulins extracted from human blood, and has an action of protecting a living body by causing antigen-antibody reactions with foreign invaders such as bacteria. In recent years, the immunoglobulin preparation has been being used for, for example, idiopathic thrombocytopenic purpura, agammaglobulinemia, the acute phase of Kawasaki disease, Guillain-Barré syndrome, and Churg-Strauss syndrome as vasculitis as well as a severe infectious disease. In addition, in the treatment of those diseases, an “IVIg therapy” involving high dose intravenous administration of immunoglobulins has been frequently employed. Recently, the IVIg therapy has attracted attention as a therapeutic method for refractory vasculitis or the like, and has been internationally regarded as important as a therapeutic method for various diseases as well. In addition, the IVIg therapy has been approved for an autoimmune disease, and in association with this, the IVIg therapies have been started for connective tissue disease and myasthenia as targets in succession. Further, the IVIg therapy has a 20-year history of Kawasaki disease treatment, and has been recently approved as being more effective in single-dose administration at 2 g/kg body weight. As described above, IVIg is extremely effective for a high-severity disease and a refractory disease of unknown cause. Further, IVIg is a useful therapeutic method also because of having virtually no side effects.
There are some hypotheses about an action mechanism of the immunoglobulin preparation. One hypothesis is such that the immunoglobulin preparation contains many kinds of antibodies including antibodies against unknown antigens and thus exert pharmacological effects. Further, another hypothesis is such that antibodies against myeloperoxidase (MPO) (anti-MPO antibodies) among the many kinds of antibodies have the effects, and in particular, many kinds of anti-MPO antibodies against a wide range of epitopes of MPO exert the pharmacological effects. What is common to both the hypotheses is that the therapeutic effect is significantly contributed by the fact that the immunoglobulin preparation is a mixture of multiple immunoglobulins, i.e., polyclonal immunoglobulins. Though there are other hypotheses, the two hypotheses given as examples are each a popular one.
An immunoglobulin preparation clinically used at present is a blood preparation, and hence always involves such a risk that an unknown pathogen such as a virus derived from a raw material may be mixed therein. In fact, a blood preparation contaminated with a pathogenic virus has caused medication-related harm, becoming a serious social issue. In addition, in association with an increase in the number of diseases to be treated, a shortage of blood serving as a raw material is predicted, and hence the immunoglobulin preparation as a blood preparation is unreliable in terms of stable supply.
Under such circumstances, in order to reduce an infection risk for a patient and reveal the process of healing by the immunoglobulin preparation, there is a demand for an artificial, synthesized immunoglobulin preparation. For producing the artificial immunoglobulin preparation, the following method has been carried out. The method involves obtaining a gene of an immunoglobulin, expressing the gene by using a recombinant DNA technology, and obtaining a purified immunoglobulin. For example, a chimeric antibody obtained by replacing only a variable region of an immunoglobulin with a mouse-derived one (Japanese Patent Application Laid-open No. Hei 5-304989), and a humanized antibody obtained by replacing only a CDR region in a variable region with a mouse-derived one (Japanese Patent Application Laid-open No. 2000-14383) can each be produced by a recombinant DNA technology. The chimeric antibody and the humanized antibody have already been put to practical use as antibody drugs. Further, as a technology for expressing an immunoglobulin gene as a normal soluble protein in host cells, there is known an example in which an immunoglobulin is expressed as a fusion protein with a chaperonin (Japanese Patent Application Laid-open No. 2004-81199). However, each of those preparations comprises a single kind of immunoglobulin, i.e., a monoclonal immunoglobulin. Further, the properties of cDNA clones are not stable, and hence the quality of purified products is not stable. Thus, the immunoglobulin preparation has problems in therapeutic effect and quality control.